This project delineates biochemical and pharmacological properties of sigma-1 receptors. Sigma-1 receptors are one-transmembrane proteins at the endoplasmic reticulum (ER) that bind neurosteroids, dextrobenzomorphans, and certain psychostimulants such as cocaine. The immunocytohistochemical studies from our previous study indicated that sigma-1 receptors are highly concentrated at the growth cones of cultured cells. Because growth cones are involved in neurite sprouting, extension, and guidance, our results suggests that sigma-1 receptors may play an important role in neuronal sprouting. Further, because certain antidepressants (SSRI) possess high to moderate affinities at sigma-1 receptors, we test a hypothesis that SSRI antidepressants may induce neuronal sprouting via sigma-1 receptors. In this fiscal year, we found that sigma-1 agonists including (+)pentazocine, and SSRI's such as fluovoxamine and imipramine, potentiate the NGF-induced neurite sprouting in PC12 cells. The potentiating effects caused by these sigma-1 agonists are blocked by NE-100, a sigma-1 receptor antagonist. In a separate experiments, we found that NGF dose- and time-dependently causes an increase of sigma-1 receptors and that the antisense treatment blocking the expression of sigma-1 receptors can attenuate the NGF-induced neurite sprouting. Taken together, our results suggest that sigma-1 receptors are crucial in NGF-induced neurite sprouting and that the SSRI antidepressants may exert their clinical efficacy by potentiating neurite sproutings in the brain via sigma1 receptors.